CN105801543B - 4- aromatic amine-coumarin derivative and preparation method thereof and medical usage - Google Patents
4- aromatic amine-coumarin derivative and preparation method thereof and medical usage Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/18—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted otherwise than in position 3 or 7
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention relates to field of medicinal chemistry, and in particular to a series of 4- aromatic amines-coumarin derivative, preparation method and medical usage is especially used to treat the drug in terms of tumour, such as breast cancer.The general structure of compound involved in the present invention is as follows, and each group definition is detailed in specification in general formula.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a series of 4- aromatic amines-coumarin derivative, preparation method
And medical usage, especially it is used for the application of anti-tumor aspect.
Background technique
Tumour is the disease characterized by abnormal cell hyperplasia out of control and diffusion.The American Cancer Society 2014 " whole world
The cancer fact and data " report display: the whole world in 2012 increases 14,000,000 cases of cancer newly altogether and has 8,200,000 people dead, wherein
Newly-increased 3,070,000 cancer patients of China simultaneously cause about 2,200,000 people dead, account for the 21.9% and 26.8% of global total amount respectively.Report
Predict that swift and violent growing trend will be presented in global cases of cancer, by 14,000,000 people in 2012, cumulative year after year to 2025 1900
Ten thousand people were up to 24,000,000 people by 2035.Cancer has become the major disease for seriously endangering human health and life, so far
Still without very satisfied treatment method, therefore it is extremely urgent to develop the efficient anti-tumor drug of low toxicity.
P cell abnormality proliferation is an important feature of cancer, can be found in almost all of cancer cell thin
The change of born of the same parents' cycle pathways, so as to cause the generation of improper oncogene and the inactivation of tumor suppressor gene or clear
It removes.The purpose of many tumor inhibitors is to block proliferation process, finally induces Apoptosis.
Cumarin is that one kind that nature is widely present has benzene a pair of horses going side by side α-pyranone structure compound, is present in not of the same race
In the plant of category, tool has been widely used, experimental studies have found that cumarin has AntiHIV1 RT activity, antitumor, anti-oxidant, anti-inflammatory etc. more
Kind pharmacological activity.Due to coumarin kind compound have molecular weight is small, synthesis is simple, bioavilability is high, pharmacological action extensively,
The features such as small toxicity, has become the research emphasis of many medicament research and development work in recent years.
The study found that many coumarin kind compounds have cytotoxic effect to the cancerous cell line of mammal.For example,
Cumarin and umbelliferone all have antitumor action in vivo and in vitro, can be by inhibiting tubulin polymerization to lure
Guided cell cycle arrest inhibits the drug combination of the growth of breast cancer system cell and other anti-newborn tumors that can enhance pair in the G1 phase
The therapeutic effect of breast cancer.
The present inventor has carried out a series of using cumarin as small point with antitumor action of parent nucleus in recent years
The design and study on the synthesis of sub- compound work, and have synthesized a series of new 4- aromatic amine-coumarin derivatives.Pharmacological experiment
Show that such compound has good anti-human breast cancer cell (MCF-7) proliferation activity.
Summary of the invention
The invention discloses coumarin kind compounds or its pharmaceutically acceptable salt with one structure of general formula.Through pharmacology
Experiments have shown that such compound has good anti-human breast cancer cell (MCF-7) proliferation activity.
General formula one:
Wherein R1Indicate H or OMe；
R2Indicate H or OMe；
R3Indicate H or OMe；
R4Indicate substituted aromatic amine, wherein the substituent group on aromatic rings includes electron-withdrawing group or electron-donating group；
R5Indicate trifluoroacetyl group or H.
Part of compounds structure of the invention is as follows:
I series:
II series:
III series:
The code name of compound is equal to compound structure corresponding to the above code name in pharmacological evaluation and embodiment.
The pharmaceutically acceptable salt that the compound of the present invention and salt are formed is also included in the present invention, one chemical combination of general formula
Object can form pharmaceutical salts: such as hydrochloride, sulfate, maleate with following salt.
Here is the partial pharmacologic test and result of the compounds of this invention:
Mtt assay tests the test of MCF-7 Cells Proliferation of Human Breast Cancer
Test method: MCF-7 breast cancer cell takes logarithm raw with the RPMI1640 culture solution culture containing 10% fetal calf serum
For Long-term cell for testing, adjustment cell density is 2 × 104A/mL is inoculated in 96 orifice plates and 100 μ is added after culture 12 hours
The pastille culture medium in the hole l/, sample ultimate density are 2 × 10-4mol/L、1×10-4mol/L、1×10-5mol/L、1×10- 6Mol/L and 1 × 10-7Mol/L, 3 multiple holes of each concentration replace testing drug as a control group with the culture medium of same volume,
20 μ l/ hole MTT (concentration 5mg/ml) are added after continuing culture 48 hours, after cultivating 4h, abandons supernatant, 150 μ of DMSO is added
The hole l/ measures every hole absorbance (A) value with enzyme mark detector at 492nm wavelength, and cell proliferation inhibition rate is calculated by formula: suppression
Rate processed=(control group A value-experimental group A value)/(control group A value-blank group A value) × 100%, and calculate IC50。
The MCF-7 Cells Proliferation of Human Breast Cancer experimental result of the compounds of this invention:
Using Tamoxifen and Raloxifene as positive control, 4- aromatic amine-coumarin derivative of synthesis is carried out
MCF-7 cell experiment, result of study shows that majority of compounds goes out preferable inhibitory activity to MCF-7 cells show, wherein changing
The activity for closing object I-3 is preferable, IC50It is 9.74 μM.
4- aromatic amine-coumarin derivative according to the present invention generally by reacting preparation as follows:
The compound of general formula one of the present invention can be prepared by following methods:
I-1~I-5:
Reactant and reaction condition: a) acetic acid, BF3-Et2, 65 DEG C, 3h；b)PPh3, MeOH, DIAD, rt,
0.5h；C) NaH, DEC, 125 DEG C, 1.5h；D) dry Isosorbide-5-Nitrae-dioxane, dry pyridine, TMSCl, rt, 1h；e)
Trifluoroacetic anhydride, 85 DEG C, 2h；f)POCl3, 60 DEG C, 2h；g)R4-NH2, Cs2CO3, EtOH, 75 DEG C, 2h.
II-1~II-6:
Reactant and reaction condition: a) Acetic anhydride, BF3-Et2, Toluene, 120 DEG C, 2h；B) NaH,
DEC, 125 DEG C, 1.5h；C) dry Isosorbide-5-Nitrae-dioxane, dry pyridine, TMSCl, rt, 1h；d)Trifluoroacetic
Anhydride, 85 DEG C, 2h；e)POCl3, 60 DEG C, 2h；f)R4-NH2, Cs2CO3, EtOH, 75 DEG C, 2h.
III-1~III-5:
Reactant and reaction condition: a) AlCl3, CH3NO2, CH3COCl, DCM, 40 DEG C, 0.5h；b)dimethyl
Sulfate, K2CO3, acetone, 50 DEG C, 6h；C) NaH, Diethyl carbonate, 125 DEG C, 1.5h；D) TsCl, Et3N,
Dry DCM, rt, 0.5h；e)R2-NH2, Cs2CO3, EtOH, 75 DEG C, 3h..
Specific embodiment (embodiment is used only to illustrate the present invention, rather than is used to limit the present invention)
The preparating example of part of compounds is as follows:
Hydrogen nuclear magnetic resonance spectrometer is that (TMS is internal standard to 500 type of Bruker AV, deuterated CDCl3Or deuterated DMSO is solvent)；
Mass spectrograph is Shimadzu GCMS-QP2010 type mass spectrograph or Mariner mass spectrograph；Experiment center pillar chromatography is all made of Qingdao Haiyang chemical industry
100-200 mesh, 200-300 mesh or the 300-400 mesh silica gel of Co., Ltd's production fix phase；Column silica gel for chromatography is 100-
200 mesh, 200-300 mesh or 300-400 mesh silica gel (Haiyang Chemical Plant, Qingdao), eluant, eluent be petroleum ether-ethyl acetate system or
Methylene chloride-methanol system.Thin-layer chromatography (TLC) uses GF254 thin layer chromatography board (Yantai Jiang You silica gel development corporation, Ltd.)；
It is petroleum ether-ethyl acetate system or methylene chloride-methanol system that system, which is unfolded, in TLC；TLC is in ZF7 type ultraviolet analysis instrument for three purposed
Display is irradiated under (Henan Gongyi Yu Hua Instrument Ltd.).Chemical reagent is that commercially available chemistry is pure or analysis net product, special out
Different explanation is outer, unprocessed direct use.
Embodiment 1
The preparation of 2,4-dihydroxyacetophenone (2)
1g resorcinol (9.09mmol) is dissolved in 10ml boron trifluoride ether by waterless operation, under nitrogen protection, heating
To 65 DEG C, it is stirred at reflux 3h, TLC detects fully reacting.After reaction solution is cooled to room temperature, reaction solution is poured slowly into ice water
In, there is yellow solid precipitation, filter, drying is recrystallized with dehydrated alcohol, obtains 0.8g yellow crystals, yield position 52.6%.ESI-
MS m/z:153.1 [M+H]+.
Embodiment 2
The preparation of Paeonolum (3)
3g intermediate 2 (19.7mmol) and 0.69g methanol (21.7mmol) are added to the anhydrous tetrahydro of 100mL by waterless operation
In furans, stirring to solution, which becomes, is clarified.It under ice bath, is slowly added to triphenylphosphine (5.67g, 21.7mmol), 4.25ml is added dropwise
DIAD (21.7mmol) finishes rear TLC and shows fully reacting.It is spin-dried for excess of solvent, after column Chromatographic purification, obtains 3.2g white
Solid, yield 86.72%.ESI-MS m/z:165 [M-H]+.
Embodiment 3
The preparation of 4- hydroxyl-ayapanin (4)
15ml diethyl carbonate is added in 1g intermediate 3 (6.02mmol) and 1.44gNaH (60.2mmol) by waterless operation
In, strong stirring, the lower 120 DEG C of reactions of nitrogen protection determine terminal with TLC.25ml ice water is added in reaction solution, NaH is destroyed,
Liquid separation after stirring 2min, organic phase discard, and water phase is extracted with ethyl acetate three times, discard organic phase, will with the hydrochloric acid of 1mol/L
Water phase pH is adjusted to 3-4, and a large amount of white solids are precipitated, and filter to obtain crude product, and 0.8g white powder, yield are obtained after column chromatographic purifying
69.57%.ESI-MS m/z:191.0 [M-H]+。
Embodiment 4
The preparation of chloro- 7 methoxy coumarin (5) of 3- trifluoroacetyl group -4-
1g intermediate 4 (5.2mmol) is dissolved in Isosorbide-5-Nitrae-dioxane of 10ml, dry pyridine is added by waterless operation
(0.86g, 11mmol), under nitrogen protection, when stirring is homogeneous to reaction liquid level, be added trim,ethylchlorosilane (0.677g,
6.24mmol), 1h is stirred under room temperature.It is added trifluoroacetic anhydride (1.31g, 6.24mmol), 85 DEG C of reflux 2h.Phosphorus oxychloride is added
(0.954g, 6.24mmol), 60 DEG C of stirring 2h..After the reaction was completed, when reaction solution is cooled to room temperature, reaction solution is slowly led
Enter in ice water, stir, 1N HCl is added by mixed liquor PH and is adjusted to 4 or so, filters, obtains 0.8g yellow solid, yield 53.69%.
ESI-MS m/z:306.0 [M+H]+。
Embodiment 5
The preparation of 3- trifluoroacetyl group -4- (para hydroxybenzene amine)-ayapanin (I-1)
0.2g intermediate 5 (0.65mmol) is dissolved in 6mLDMF, 0.4g cesium carbonate (1.3mmol) and para hydroxybenzene amine is added
(0.07g, 0.65mmol), 85 DEG C of reflux 2h, TLC show fully reacting.It is cooling, insoluble matter is filtered, filtrate is spin-dried for, passes through column
Chromatographic purification obtains yellow crystals 0.1g, yield 37.03%.1H NMR(DMSO-d6, 300MHz) and δ: 11.48 (s, 1H), 9.71
(s, 1H), 7.53 (d, 1H), 7.06 (d, 2H), 6.77 (t, 4H), 3.83 (s, 3H) ppm；ESI-MS m/z:380.1 [M+H]+
Embodiment 6
The preparation of 3- trifluoroacetyl group -4- (3- hydroxyl -4- aminoanisole)-ayapanin (I-2)
The synthesis of concrete operations reference compound (I-1) is put into 0.2g intermediate 5 (0.65mmol), 3- hydroxyl -4- methoxy
Base aniline (0.09g, 0.65mmol), 0.4g cesium carbonate (1.3mmol) obtain 0.12g yellow solid, yield 41.37%.1H NMR
(DMSO-d6, 300MHz) and δ: 10.52 (s, 1H), 8.89 (d, 2H), 8.31 (d, 1H), 7.10 (t, 3H), 6.94 (s, 1H),
3.88 (s, 3H), 3.76 (s, 3H) ppm；ESI-MS m/z:410.2 [M+H]+
Embodiment 7
The preparation of 3- trifluoroacetyl group -4- (para-fluoroaniline)-ayapanin (I-3)
The synthesis of concrete operations reference compound (I-1) is put into 0.2g intermediate 5 (0.65mmol), para-fluoroaniline
(0.072g, 0.65mmol), 0.4g cesium carbonate (1.3mmol) obtain 0.08g yellow solid, yield 29.41%.1H NMR
(DMSO-d6, 300MHz) and δ: 11.08 (s, 1H), 7.72 (d, 1H), 7.35 (m, 4H), 6.99 (d, 1H), 6.87 (d, 1H),
3.87 (s, 3H) ppm；ESI-MS m/z:382.1 [M+H]+
Embodiment 8
The preparation of 3- trifluoroacetyl group -4- (3,4- methylene dioxo group aniline)-ayapanin (I-4)
The synthesis of concrete operations reference compound (I-1) is put into 0.2g intermediate 5 (0.65mmol), 3,4- (methylenedioxy)s
Base aniline (0.089g, 0.65mmol), 0.4g cesium carbonate (1.3mmol) obtain 0.09g yellow solid, yield 31.14%.1H
NMR(DMSO-d6, 300MHz) and δ: 11.16 (s, 1H), 7.70 (d, 1H), 6.98 (m, 3H), 6.90 (d, 1H), 6.78 (d, 1H),
6.06 (s, 2H), 3.85 (s, 3H) ppm；ESI-MS m/z:408.1 [M+H]+
Embodiment 9
The preparation of 3- trifluoroacetyl group -4- (P-nethoxyaniline)-ayapanin (I-5)
The synthesis of concrete operations reference compound (I-1) is put into 0.2g intermediate 5 (0.65mmol), P-nethoxyaniline
(0.079g, 0.65mmol), 0.4g cesium carbonate (1.3mmol) obtain 0.07g yellow solid, yield 25.09%.ESI-MS m/z:
395.1[M+H]+
Embodiment 10
The preparation of 2- acetyl group -4- metoxyphenol (6)
P methoxy phenol 3.0g (24mmol) is dissolved with the toluene solution 24ml newly steamed, under nitrogen protection, then successively
The boron trifluoride ether of acetic anhydride 1.5ml and 12ml is added.Flow back 2h, determines terminal with TLC, is cooled to room temperature to reaction solution
Afterwards, it is slowly poured into ice water, there is solid precipitation, filter, drying, then recrystallized with dehydrated alcohol, 2.6g yellow solid is obtained,
Yield is 66.67%.ESI-MS m/z:167.0 [M-H]+。
Embodiment 11
The preparation of 4- hydroxyl -6- methoxy coumarin (7)
The synthesis of concrete operations reference compound 4 puts into 2g intermediate 6 (12.04mmol) and 2..88gNaH
(120.4mmol), 30ml diethyl carbonate obtain 1.6g white powder, yield 69.57%.ESI-MS m/z:191.0 [M-H]+
Embodiment 12
The preparation of the chloro- 6- methoxy coumarin (8) of 3- trifluoroacetyl group -4-
The synthesis of concrete operations reference compound 5 is put into intermediate 7 (1g, 5.2mmol), Isosorbide-5-Nitrae-dioxane of 10ml,
Under nitrogen protection, when stirring is homogeneous to reaction liquid level, trim,ethylchlorosilane is added in dry pyridine (0.86g, 11mmol)
(0.677g, 6.24mmol) stirs 1h under room temperature.It is added trifluoroacetic anhydride (1.31g, 6.24mmol), 85 DEG C of reflux 2h.It is added
Phosphorus oxychloride (0.954g, 6.24mmol), 60 DEG C of stirring 2h..Obtain 0.6g yellow solid, yield 40.27%.ESI-MS m/z:
306.0[M+H]+
Embodiment 13
The preparation of 3- trifluoroacetyl group -4- (3- hydroxy-4-methyl aniline) -6- methoxy coumarin (II-1)
The synthesis of concrete operations reference compound (I-1) is put into 0.2g intermediate 8 (0.65mmol), 3- hydroxy-4-methyl
Aniline (0.079g, 0.65mmol), 0.4g cesium carbonate (1.3mmol) obtain 0.06g yellow solid, yield 21.05%.1H NMR
(DMSO-d6, 300MHz) and δ: 10.63 (s, 1H), 9.14 (s, 1H), 7.94 (d, 1H), 7.46 (d, 1H), 7.38 (d, 1H),
7.27 (d, 1H), 6.93 (d, 1H), 3.90 (s, 3H), ppm；ESI-MS m/z:410.2 [M+H]+
Embodiment 14
The preparation of 3- trifluoroacetyl group -4- (3- hydroxyl -4- aminoanisole) -6- methoxy coumarin (II-2)
The synthesis of concrete operations reference compound (I-1) is put into 0.2g intermediate 8 (0.65mmol), 3- hydroxyl -4- methoxy
Base aniline (0.09g, 0.65mmol), 0.4g cesium carbonate (1.3mmol) obtain 0.075g yellow solid, yield 25.86%.1H
NMR(DMSO-d6, 300MHz) and δ: 8.02 (s, 1H), 7.46 (d, 1H), 7.23 (d, 2H), 6.83 (d, 2H), 6.65 (d, 2H),
6.2 (m, 1H), 3.80 (s, 3H), 3.78 (s, 3H) ppm；ESI-MS m/z:410.2 [M+H]+
Embodiment 15
The preparation of 3- trifluoroacetyl group -4- (3,4- methylene dioxo group aniline) -6- methoxy coumarin (II-3)
The synthesis of concrete operations reference compound (I-1) is put into 0.2g intermediate 8 (0.65mmol), 3,4- (methylenedioxy)s
Base aniline (0.089g, 0.65mmol), 0.4g cesium carbonate (1.3mmol) obtain 0.08g yellow solid, yield 27.68%.1H
NMR(DMSO-d6, 300MHz) and δ: 10.52 (s, 1H), 7.65 (d, 1H), 7.39 (m, 2H), 6.97 (d, 1H), 6.89 (d, 1H),
6.74 (d, 1H), 6.06 (s, 2H), 3.76 (s, 3H) ppm；ESI-MS m/z:408.1 [M+H]+
Embodiment 16
The preparation of 3- trifluoroacetyl group -4- (para-fluoroaniline) -6- methoxy coumarin (II-4)
The synthesis of concrete operations reference compound (I-1) is put into 0.2g intermediate 8 (0.65mmol), para-fluoroaniline
(0.072g, 0.65mmol), 0.4g cesium carbonate (1.3mmol) obtain 0.055g yellow solid, yield 20.76%.1H NMR
(DMSO-d6, 300MHz) and δ: 10.54 (s, 1H), 7.64 (d, 1H), 7.41 (d, 2H), 7.35 (d, 4H), 3.76 (s, 6H)
ppm；ESI-MS m/z:382.1 [M+H]+
Embodiment 17
The preparation of 3- trifluoroacetyl group -4- (P-nethoxyaniline) -6- methoxy coumarin (II-5)
The synthesis of concrete operations reference compound (I-1) is put into 0.2g intermediate 8 (0.65mmol), P-nethoxyaniline
(0.079g, 0.65mmol), 0.4g cesium carbonate (1.3mmol) obtain 0.08g yellow solid, yield 28.67%.1H NMR
(DMSO-d6, 300MHz) and δ: 10.74 (s, 1H), 7.53 (s, 1H), 7.38 (m, 2H), 7.21 (d, 2H), 6.99 (d, 2H),
3.76 (s, 3H), 3.70 (s, 3H) ppm；ESI-MS m/z:395.1 [M+H]+
Embodiment 18
The preparation of 3- trifluoroacetyl group -4- (para hydroxybenzene amine) -6- methoxy coumarin (II-6)
The synthesis of concrete operations reference compound (I-1) is put into 0.2g intermediate 8 (0.65mmol), para hydroxybenzene amine
(0.079g, 0.65mmol), 0.4g cesium carbonate (1.3mmol) obtain 0.06g yellow solid, yield 21.50%.1H NMR
(DMSO-d6, 300MHz) and δ: 10.78 (s, 1H), 9.76 (s, 1H), 7.50 (s, 1H), 7.38 (m, 2H), 7.08 (d, 2H),
6.81 (d, 2H), 3.69 (s, 3H) ppm；ESI-MS m/z:395.1 [M+H]+
Embodiment 19
The preparation of 2,4,6- trihydroxy-acetophenones (9)
12.603g phloroglucin (100mmol) and 26g aluminium chloride (200mmol) are dissolved in 200mlDCM by waterless operation
In, after reaction solution dissolved clarification, 12g nitromethane (200mmol) and chloroacetic chloride (8.63g, 110mmol) are sequentially added, after finishing,
Reacting liquid temperature is raised to 40 DEG C, stirs 40min.After the reaction was completed, reaction solution is poured slowly into ice water, it will with dilute hydrochloric acid
The PH of mixed liquor is adjusted to 4 or so, discards organic phase, and water phase is extracted with ethyl acetate, washing, and the dry 30mim of anhydrous sodium sulfate subtracts
Pressure distillation spins off ethyl acetate, obtains 15g white solid, yield 71.36% by column chromatography for separation.ESI-MS m/z:
169.1[M+H]+
Embodiment 20
The preparation of Xanthoxylin (10)
Waterless operation puts into 5g intermediate 6 (26.85mmol) in 80ml acetone, and 7.5g potassium carbonate is added
(54.35mmol) and 5.25ml dimethyl suflfate (20mmol), reaction solution are warming up to 50 DEG C, react 6 hours, and reaction is completed
Afterwards, extra acetone is removed by vacuum distillation, is purified by column chromatography for separation, obtain white solid, yield is
81.36%.ESI-MS m/z:195.0 [M-H]+
Embodiment 21
The preparation of 4- hydroxyl -5,7- dimethoxycoumarin (11)
The synthesis of concrete operations reference compound 4 puts into 1g intermediate 10 (5.1mmol) and 1.22gNaH (51mmol),
15ml diethyl carbonate obtains 0.8g white powder, yield 70.79%.ESI-MS m/z:223.0 [M+H]+
Embodiment 22
The preparation of (5,7- dimethoxycoumarin) -4- p-methyl benzenesulfonic acid ester (12)
2g intermediate 11 (9mmol) is dissolved in the anhydrous DCM of 20ml, is added to the stupid sulphonic acid ester of first (1.71g, 9mmol),
Under room temperature, 1h is stirred.TLC is detected after the reaction was completed, and vacuum distillation removes extra DCM, is obtained by Zhu's chromatography, 2.9g
White solid, yield 78.16%.ESI-MS m/z:399.0 [M+Na]+
Embodiment 23
The preparation of 4- (3- hydroxy-4-methyl aniline) -5-7- dimethoxycoumarin (III-1)
The synthesis of concrete operations reference compound (I-1) is put into 0.2g intermediate 12 (0.53mmol), 3- hydroxyl -4- first
Base aniline (0.065g, 0.53mmol), 0.4g cesium carbonate (1.3mmol) obtain 0.012g yellow solid, yield 4.53%.1H
NMR(DMSO-d6, 300MHz) and δ: 9.13 (s, 1H), 7.10 (d, 1H), 6.73 (d, 1H), 6.62 (d, 1H), 6.52 (d, 2H),
4.88 (s, 1H), 3.95 (s, 3H), 3.82 (s, 3H), 2.11 (s, 3H) ppm；ESI-MS m/z:328.1 [M+H]+
Claims (3)
1. a kind of compound or its pharmaceutically acceptable salt, the compound structure are as follows:
I series:
Wherein R4It represents:
2. a kind of compound or its pharmaceutically acceptable salt, the compound structure are as follows:
II series:
Wherein R4It represents:
3. compound described in any one of claims 1 to 2 is used as the purposes for preparing anti-breast cancer medicines.
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| WO2000039120A2 (en) * | 1998-12-30 | 2000-07-06 | Signal Pharmaceuticals, Inc. | Compounds and methods for modulation of estrogen receptors |
| WO2001049673A2 (en) * | 1999-12-30 | 2001-07-12 | Signal Pharmaceuticals, Inc. | Compounds and methods for modulation of estrogen receptors |
| CN103450133A (en) * | 2013-09-16 | 2013-12-18 | 中国药科大学 | Scopoletin derivatives with anti-tumor activity, and preparation method and application thereof |
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2016
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| WO2000039120A2 (en) * | 1998-12-30 | 2000-07-06 | Signal Pharmaceuticals, Inc. | Compounds and methods for modulation of estrogen receptors |
| WO2001049673A2 (en) * | 1999-12-30 | 2001-07-12 | Signal Pharmaceuticals, Inc. | Compounds and methods for modulation of estrogen receptors |
| CN103450133A (en) * | 2013-09-16 | 2013-12-18 | 中国药科大学 | Scopoletin derivatives with anti-tumor activity, and preparation method and application thereof |
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| Design, synthesis and biological evaluation of novel 3-substituted 4-anilino-coumarin derivatives as antitumor agents;Guoshun Luo等;《Bioorganic & Medicinal Chemistry Letters》;20170107;第27卷;第867-874页 |
| Investigation of (E)-3-[4-(2-Oxo-3-aryl-chromen-4-yl)oxyphenyl]acrylic Acids as Oral Selective Estrogen Receptor Down-Regulators;Sébastein L. Degorce等;《J. Med. Chem.》;20150319;第58卷;第3522-3533页 |
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